Longevity Cook Book

Longevity Cook Book menu draft

My colleagues and I would like to launch the Longevity Cook Book crowdfunding campaign in upcoming three months.

We would like to raise fuding to create a book that will tell the story about what longevity depends on, what processes are going on in our bodies during aging and how they can be slowed down, dieting in the right way, based on the current scientific knowledge. The book will contain the most up-to-date research data on the beneficial properties of various foods, their longevity effects and abilities to prevent different age-related diseases.

Longevity Cook Book will give you the special recipes, developed with the help of professional chefs, on how to cook longevity-boosting dishes from the healthiest ingredients possible.

Besides the recipes, the book will tell you how to “cook” longevity in terms of science. I will explain the existing directions in aging research and the most promising experiments that need to be carried out to make a truly long and healthy life a reality.

Here’s the Longevity Cook Book plan:

Part 1

  • The role of diet in health and longevity. I will describe the diets that increase longevity and prevent age-related pathologies (with proof in humans and model animals)
  • Physiology of nutrition. I will explain how food is digested, how the nutrients are absorbed in the intestines, how they enter blood stream, what they do inside the cells. There will be some pretty pictures to illustrate all of that.
  • Brief and easy-to-understand description of aging mechanisms and the mechanisms of age-related pathologies (like cardiovascular diseases, diabetes, etc.) and how diet can influence those mechanisms

Part 2

Description of the healthy foods including scientific papers, illustrating why they are healthy, and biological mechanisms that those foods influence

Part 3

Longevity Menu. Dishes made with longevity foods cooked the healthiest ways accompanied by pretty pictures of the dishes.

Part 4

“Cooking” longevity. I will describe the main approaches to solving the problem of aging and the most promising experiments.

How do you like the idea? Would you be interested in reading such a book?

For the crowdfunding project to be successful it has to have a powerful start, therefore I’d like to agree on reposting the campaign when it launches in advance.

I call upon everybody to, please, let me know, who would be up to spreading the word about this project when the time comes.

If you have some nice amount of people following you on twitter or other social networks, I’ll be happy to collaborate.

I also welcome advice on how to engage a larger audience. Maybe you have some journalists or bloggers that you know?

I present a draft of a possible layout of one of the pages.

There will be many different icons that tell you various bits of information about the dish. In particular on this page a face means the research on the given type of food was done in humans, a mouse – on mice, a test tube – on cell cultures.

We haven’t yet put together the pictures of aging mechanisms, but we will definitely do it.


Filed under Longevity Cook Book, Uncategorized

Longevity Gene Therapy – Updated Projects

While discussing the longevity gene therapy project we encountered various questions and observations that prompted us to broaden the project and slightly change it. Generally, all the comments can be reduced into 5 main points:

  1. You need to enlarge the list of therapeutic genes by adding to it this and that.
  2. You want to use too many genes; therefore you need to make the project simpler by keeping only the most effective genes
  3. If you apply all the genes at the same time, some of them may cancel out the effects of other genes.
  4. Will it be safe to use viral vectors to deliver genetic constructs?
  5. How safe are therapeutic genes for the body?

Some of the observations were of completely opposite nature, so we decided to do 2 versions of the project. One of them is for aging geneticists. In it we almost double the list of the genes extending lifespan. This project will allow testing many poorly studied genes, but promising in terms of aging. Besides, some unexpected results can be obtained, which is always valuable.

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Popular Lectures on Gene Therapy

We have put together a list of popular science video lectures on gene therapy – one of the most promising molecular medicine directions. What makes this approach different is that nucleic acid molecules, DNA and RNA, are used as therapeutic agents.

To have the most general idea about the principles of gene therapy you can watch this video

The lecture by Dr. Hans-Peter Kiem from Fred Hutchinson Cancer Research Center at University of Washington provides more detailed information about the main approaches utilized by gene therapy, nucleic acid delivery methods into the cells and also the diseases that use gene therapy for treatment

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We Can Learn a Lot from Yeast How to Slow Down Aging

Valter Longo's lecture

Dr. Valter Longo hold the record of yeast lifespan extension. He was able to increase longevity of this species 10 fold. This a one of the most remarkable results in longevity science. Here Dr. Longo is giving us a lecture on yeast genetics. Let me summarize what he told us.

Yeast are unicellular organisms. They have 6,000 genes packed in 16 chromosomes. They divide every 90 minutes. They are one of the widely used model animals for research, and not only aging research, because they are safe, quite easy to handle and inexpensive. One of the best feature for aging research is that their lifespan is really short. I will use a vague term – about a week, because it depends on the way how you measure their longevity.

There are two major methods to see how long yeast live – replicative and chronological lifespan analyses. The first one looks at the dividing mother cell and determines how many times the  division happened. People can distinctly distinguish the newly formed daughter cell and the mother cell, because daughter cells are smaller in size. This work is really tedious, because it relies on manual sorting of the cells. None the less, this is how we can measure the yeast health span – the period of time when the cell is able to give progeny. After it has no more “babies” it doesn’t die though immediately (humans don’t too), however this assay doesn’t include the time when the cell remains alive.

The chronological lifespan analysis looks at how long the non-diving colony of cells live. The number of cells alive at each particular moment is estimated by the number of colonies that they form on a plate with nutrients that allows growth so the colonies can be visible. In order to bring the yeast to a non-diving state, they are stripped of nutrients in the medium, so they switch to a growth arrest state to ensure survival rather than reproduction. This is called a post-diauxic phase. Their survival is approximately 6 days in this state. And the metabolic rates are very high.

One of the ways to extend yeast lifespan is to remove all nutrients from the medium and simply substitute it with water. They will then enter a stationary phase when their metabolic rate is reduced, which allows better stress resistance and longer survival, about 17 days.

There is an even great lifespan extension mode that allow yeast cells live years – spore state. If you put the cells in 1% potassium acetate, the cells will convert into spores and will be able to live several year. They will be dormant and highly stress resistant. I can’t say anything about their metabolic rate though, and do you know why? Because nobody in the world in studying that. Can you believe it? I was so surprised. The reason why is I guess because of lack of funding. So, there is no person or agency in the world that is interesting in learning how an organism that normally lives just 6 days can manage to stay alive for several years. This is just so hard to grasp for me.

In yeast the best gene found so far for longevity interventions is Sch9. It is an analog of the S6 kinase that mammalian cells have to sense nutrients and respond in growth and division. Sch9 is more central in nutrient signaling than tor1. This is probably true for all eukaryotes. We know interventions for mTOR, which is a drug that suppresses mTOR activity, called rapamycin. Apparently, there maybe even more potent drugs that slow down aging that work on the S6 kinase. They haven’t been identified yet.

Another very interesting genes in yeast is rash. It senses glucose. Mutant yeast that don’t have this gene also live longer, but not as long as the “top record holder” Sch9 mutants. Sch9 can be seen as a conductor that orchestrates what is happening in the cell. I loved this beautiful analogy that Dr. Longo used, because it really makes you understand why sometimes if a trumpet plays really loud (and a trumpet is a very nice instrument), the whole orchestra doesn’t sound better. It’s the same when you activate one thing, one very good thing on its own, but all together you don;t see an improvement in life extension. The reason is because you need to influence the “conductor”, a gene like Sch9 in yeast.

Sch9 operates through msn2 and msn4 genes that pass on the orders of the “conductor” and activate various genes like cytoplasmic catalase T (anti-oxidative stress gene), DNA damage response genes, heat shock protein 12, trehalose phosphate phosphatase (stress protectant) and others. Also MnSOD (superoxide dismutase, anti-oxidant enzyme) is required for the longevity effect of switching off Sch9 to take place. This effect is 3 times lifespan extension, by the way. Over expressing SOD can only give 10-30% lifespan extension, so it’s crucial when it works together with the “conductor”.

Mutations in tor1 and school that delay aging cause a metabolic shift from the catabolism of glucose and ethanol to respiration and production of glycerol. Glycerol for yeast appears to be a neutral carbon course that does not promote pro-aging phenotype. It’s kind of like “good fat”, like olive oil. Mitochondrial superoxide is a major mediator of DNA mutations, aging, death, and the release of nutrients. Mutations in the Sch9 or Ras pathways extend life span in part by increasing protection against mitochondrial superoxide.

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Fund Anti-Cancer Research and Make Drugs Cheaper at the Same Time

This is a very cool crowdfunding campaign – you can help create a new cancer drug and at the same make it much cheaper. How? The researchers will not patent the drugs. Like polio vaccine, which was never patented, therefore it was widely available. Check out the website and the video. I loved it and made a donation of $50, because I find projects like this can change the existing paradigm in healthcare when the existing drugs are just deadly expensive. I encourage you to support the project and share it with your friends.

By the way, in aging there are also drugs that can never be patented like aspirin, metformin and rapamycin, but may well extend our lifespan. No pharmaceutical company will be interested in looking at substances that can’t be patented, but this could make our lives longer and healthier.


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Role of Mitochondria in Disease

Mitochondria and diseaseThere are tree lectures about the mitochondria in my course. Dr. Pinchas Cohen, the Dean of Davis School of Gerontology, talked about the role of mitochondria in disease and pathology.

Mitochondria have essentially three major functions. They are responsible for cellular respiration, integration of apoptotic signals, which means they control cell death, and production of reactive oxygen species (ROS). Mitochondrial function declines with age as a result of accumulated mutations in the mitochondrial DNA. Mitochondrial disfunction is common in diseases, such as diabetes, neurodegenerative pathologies and cancer.

Interestingly, Dr. Cohen mentioned that there were only three Nobel prizes for research in mitochondrial biology. He anticipates that quite soon there will be a Prize awarded to mitochondria research.

Mitochondria are very different in different tissues. They vary in size, numbers, histologically and in proteins they have. Energy production levels also vary quite significantly. This is due to differences in cellular environment in different cell types. Mitochondria adapt to the surrounding situation.

Mitochondrial DNA can be used to track ancestral origins of the population. For example, all Ashkenazi jews, and there are approximately 8 million of them on the planet can be tracked down to 4 Italian women who lived around 2 thousand years ago.

There are numerous diseases associated with mutations in mitochondrial DNA. It is absolutely not clear why so specific phenotypes are associated with given mtDNA mutations. For exapample, the DEAF 1555 mutation is extremely rare (only 50 families in the world) and only affects the inner ear and nothing else. It causes deafness. However a close mutation is more widely spread and causes both deafness and diabetes. It is absolutely not clear why this happens.

The most common mutation is MELAS 3243. It stands for myopathy, encephalopathy, lactic acedosis and stroke-like episodes. The severity of pathology differs significanly in individuals who have this mutation. Some may only have mild metabolic disfunction, but others would have severe diabetes.

ADPD mutations contribute to Alzheimer’s and Parkinson’s diseases. There’s also a whole cluster of mutations responsible for elevated risk of getting prostate cancer. There are mutations responsible for muscle/cardiac/renal and neuro abnormalities and autism-spectrum disorders.

Dr. Cohen believes that upto 90% of healthcare costs can be reduced by diet and exercise. Unfortunately, lifestyle changes are rarely enforceable.

Mitochondrial dysfunction is recognized to be a contributing factor in malignancy. Specifically, it relates to a transition from aerobic to glycolytic metabolism, resistance to mitochondrial apoptosis, accumulation of mitochondrial mutations and increased levels of mitochondrial transcripts of various lengths in certain cancers, in particular from the 16S rRNA.

Diet and excersise significanly improve mitochondrial function. There are also 3 drugs that are PPAR-gamma agonists that improve mitochondrial function. As do drugs like GLP1, insulin and metformin. Of course, it is not a good idea to supplement yourself with insulin, however metformin seems very promising, especially given the recent publication where patients who have diabetes and take metformin have better survival curves than healthy controls.

When UCP-2 protein levels go down, mitochondrial function is impaired, because the glucose/fatty acid metabolism ratio is changed.

A recent paper showed that mitochondria trancriptome is in fact very interesting and further studies may shed light onto the so far unknown mechanisms of mitochondria function regulation. For example, this paper showed differences in the 13 protein expression ranging from organ to organ. There were also sense and anti-sense RNA detected, as well as small RNAs with unclear roles. Apparently there’s much more to the story of mitochondrial genome and its function that we now understand.

There was a paper by Andrew Dillin and his team that posited there are mitokines that are secreted in the brain, but operate in the gut. It is not known though what mitokines are.

Mitochondria do produce small peptides that influence cellular function. Dr. Cohen has discovered a peptide called humanin. Apparently, higher levels of humanin are associated with less Alzheimer’s disease and less cardio vascular disease. IGF1 decreases humanin levels. More research should be done in mitochondria-derived peptides, since it seems that they may play quite important role in aging and disease.

On a side note when talking about diabetes Dr. Cohen mentioned there are only 5 types of diets: reduced amino acid intake (less meat), reduced carbohydrate intake, reduced fats, low calorie diet and intermittant fasting. He believes that it may be a good idea to adjust one’s diet according to the certain disease risks. For example, if a person has elevated cancer risk, then they should consume less amino acids, and those with higher cardiovascular risks may want to stay away from carbs-enriched foods. These are of course speculations. The only diet that was proven to be beneficial in terms of reducing disease risk is the Midetteranean diet.


Filed under Biology of Aging

How to Win the Palo Alto Longevity Prize

$1,000,000 is the recently announced prize by Joon Yun, a Palo Alto-based entrepreneur, who is willing to donate this amount of money as an incentive to end aging. Half of the million will be given to the team of researchers who are able to extend lifespan by 50% in a model animal, and the other half – to those who manage to “demonstrate that it can restore homeostatic capacity (using heart rate variability as the surrogate measure) of an aging reference mammal to that of a young adult.”

Performing the experiment described below will secure winning the Homeostatic Capacity half of the Prize. The probability of the proposed study to demonstrate significant improvement of the heart rate variability marker is extremely high, because parabiosis was already shown to promote functional parameters of the nervous and cardiovascular systems. Now, by using a young clone we can reduce all possible immunological adverse reactions to the minimum and see how the old animal rejuvenates because of the circulating systemic factors produced by the young clone. Check out the detailed prize-winning study description here.

Heterochronic parabiosis for old mouse rejuvenation

One of the most productive paradigms of aging suppression is based on rejuvenation of blood-borne systemic regulatory factors. Parabiosis, which is characterized by a shared blood supply between two surgically connected animals, may provide such experimental paradigm. We propose to use heterochronic parabiosis, the parabiotic pairing of two animals of different ages, for old mouse rejuvenation. Heterochronic parabiosis also provides an experimental system to identify systemic factors influencing the aging process of the old mouse and promoting its longevity. The optimal rejuvenation effect of heterochronic parabiosis can be achieved by using cloned (genetically identical) animals. This will help avoid potential side effects caused by immune response.

Parabiosis experiment chart

The early reported studies that used heterochronic parabiosis in rodent models to study lifespan regulation provided evidence of significant benefit to the older parabiont (reviewed in Conboy et al., 2013; Eggel, Wyss-Coray, 2014). Heterochronic parabiosis resulted not only in lifespan extension of the older parabiont (Ludwig & Elashoff, 1972), but it also promoted functional and regeneration potential in the aging central nervous system (Ruckh et al., 2012; Villeda et al., 2011), muscle and liver (Conboy et al., 2005), reversed age-related cardiac hypertrophy (Loffredo et al., 2013) and some other age-related parameters. Thus heterochronic parabiosis experiments indicate that blood-borne signals from a young circulation can significantly impact the function of aging tissues. The implication of these findings is that old tissues might make their function almost as well as young tissues if, by means of systemic influences, the molecular pathways could be ‘rejuvenated’ from an old state to a young state.

The optimum rejuvenation effect of heterochronic parabiosis can be achieved using genetically identical animals. Genetically identical non-model organisms of different age can only be obtained by cloning. Interestingly, that there are no investigations of heterochronic parabiosis of cloned animals.

The aim of the project is the comprehensive investigation of rejuvenation potential of cloned mice heterochronic parabiosis.

Research plan:

At first we will perform cloning of adult (1-year-old) mice using technique for improved success cloning rate (Mizutani et al., 2014).

The study is performed in five groups of animals:

  1. Pair of cloned young and old heterochronic parabionts.
  2. Pair of young and old heterochronic parabionts (not cloned).
  3. Pair of two young parabionts.
  4. Pair of two old parabionts.
  5. Intact control animals.

The parabiosis is established at the age of 18 months for old partners and 2 month for the young ones. The detailed life span assay reveals the influence of heterochronic parabiosis with young clone on cardiovascular, nervous, respiratory, skeletal and muscular systems. The lifespan assay shows the young clone parabiosis impact on longevity of older partner.

In addition, systemic factors, which influence the aging process of the old mouse and promote its longevity and rejuvenation, are revealed.

Expected results:

  • Study of heterochronical parabiosis effects on the process of cell and tissue aging, development of age-related diseases, and other age-related parameters including organismal longevity of the old mouse
  • Identification of rejuvenation factors
  • Results of the experiment may be used for development of human rejuvenation approach by systemic regulation of the aging process


Filed under Biology of Aging